The IL-15-Based ALT-803 Complex Enhances FcγRIIIa-Triggered NK Cell Responses and In Vivo Clearance of B Cell Lymphomas

Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor c...

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Published in:Clinical cancer research 2016-02, Vol.22 (3), p.596-608
Main Authors: Rosario, Maximillian, Liu, Bai, Kong, Lin, Collins, Lynne I, Schneider, Stephanie E, Chen, Xiaoyue, Han, Kaiping, Jeng, Emily K, Rhode, Peter R, Leong, Jeffrey W, Schappe, Timothy, Jewell, Brea A, Keppel, Catherine R, Shah, Keval, Hess, Brian, Romee, Rizwan, Piwnica-Worms, David R, Cashen, Amanda F, Bartlett, Nancy L, Wong, Hing C, Fehniger, Todd A
Format: Article
Language:English
Subjects:
Animals
Antibody-Dependent Cell Cytotoxicity - drug effects
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cytotoxicity, Immunologic - drug effects
Disease Models, Animal
Drug Synergism
Gene Expression Regulation, Neoplastic - drug effects
Granzymes - genetics
Granzymes - metabolism
Humans
Interferon-gamma - biosynthesis
Killer Cells, Natural - immunology
Killer Cells, Natural - metabolism
Lymphoma, B-Cell - drug therapy
Lymphoma, B-Cell - immunology
Lymphoma, B-Cell - metabolism
Lymphoma, B-Cell - pathology
Mice
Mice, Knockout
Perforin - genetics
Perforin - metabolism
Proteins - pharmacology
Receptors, IgG - metabolism
Rituximab - pharmacology
Xenograft Model Antitumor Assays
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Summary:Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. We hypothesized that ALT-803 would enhance anti-CD20 mAb-directed NK-cell responses and antibody-dependent cellular cytotoxicity (ADCC). We tested this hypothesis by adding ALT-803 immunostimulation to anti-CD20 mAb triggering of NK cells in vitro and in vivo. Cell lines and primary human lymphoma cells were utilized as targets for primary human NK cells. Two complementary in vivo mouse models were used, which included human NK-cell xenografts in NOD/SCID-γc (-/-) mice. We demonstrate that short-term ALT-803 stimulation significantly increased degranulation, IFNγ production, and ADCC by human NK cells against B-cell lymphoma cell lines or primary follicular lymphoma cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality. Moreover, in two distinct in vivo B-cell lymphoma models, the addition of ALT-803 to anti-CD20 mAb therapy resulted in significantly reduced tumor cell burden and increased survival. Long-term ALT-803 stimulation of human NK cells induced proliferation and NK-cell subset changes with preserved ADCC. ALT-803 represents a novel immunostimulatory drug that enhances NK-cell antilymphoma responses in vitro and in vivo, thereby supporting the clinical investigation of ALT-803 plus anti-CD20 mAbs in patients with indolent B-cell lymphoma.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-15-1419